SUBSTITUTED PHOSPHONATES, THE PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: The present invention relates to novel phosphonates substituted by dialkylphenol group of formula (I), in which G, X<1>, X<2>, D, Y, Z<1> and Z<2> are defined in Claim 1, as well as their preparations and the pharmaceutical compositions comprising them.

Description: SUBSTITUTED PHOSPHONATES, THE PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM This invention relates to novel phosphonates substituted with a dialkyl phenol moiety and the processes for their preparation. It further relates to pharmaceutical compositions containing these compounds and their therapeutic use in diseases in which reactive oxygen radicals have been implicated and more specifically in the treatment of atherosclerosis. Reactive oxygen species are involved in a number of pathologies, pharmacological and clinical evidence have been firmly established in the following cases (Halliwell, B. et al. "Role of Free Radicals and Catalytic Metal Ions in Human Disease: an Overview", Methods Enzymol.1 , 1-85, 1990): - inflammatory and immunologic injuries (autoimmune diseases, rheumatoid arthritis), - ischemia/reperfusion injury, - radiation injury, - premature ageing, - Parkinson's and Alzheimer's diseases, - cancer and anti-cancer treatments, - conditions associated with impaired blood circulation such as intermittent claudication, excessive platelet aggregation, myocardial infarction and atherosclerosis. In these pathological situations antioxidant products would be useful as therapeutic agents. The tests performed by the inventors show that the phosphonates of formula (I) through their dialkyl phenol and phosphonate moieties display potent antioxidant activities and therefore offer this therapeutic potential. In the particular case of atherosclerosis, it is now clearly proven that cholesterol carried in LDL is the most atherogenic form of plasma cholesterol. On the other hand current research shows that the uptake of oxidized LDL by macrophages leads to the formation of lipid-laden foam cells, which is the first step in the development of atherosclerosis. Numerous epidemiological studies have now firmly established that high blood cholesterol is a major risk factor for coronary heart disease. Based on the above, it can be postulated that the combination of a cholesterol lowering regimen with an antioxidant treatment might be more effective than either one. A drug which possesses the dual hypocholesterolemic and antioxidant property could therefore be highly effective in the treatment of atherosclerosis. The phosphonate compounds (I) of this invention inhibit markedly the synthesis of cholesterol in human cell lines similarly to the HMGCoA reductase enzyme inhibitors (lovastatin, simvastatin) which are potent hypocholesterolemic drugs in man. The combination of their antioxidant and hypocholesterolemic activities confer to the phosphonates of this invention the potential for treating diseases associated with elevated cholesterol levels and pathological lipid oxidation. Furthermore, the lipophilicity of these compounds predicts that they will become incorporated in the LDL and protect these particles against the damages caused by oxidative species. The generic structure of the compounds of the present invention is represented by formula (I) where - X-, χ2 identical or different are straight or branched C\ to C alkyl groups, - Y is O or S, - Z-, 7?-, identical or different, are: - OR where R is H, a straight or branched Ci-Cβ alkyl group, - NR1R here W~, R^, identical or different are H or a straight or branched C\- C6 alkyl group, - _l.-, 7?- together may form a C2-Cg alkylidenedioxy group, - G is OH or a bioprecursor thereof; D is a saturated or unsaturated Cj-Ci \ alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be substituted by one or more halogen atoms (F, Cl or Br), C - alkyl, phenyl, hydroxy or acyl oxy groups, and salts, solvates and hydrates thereof. Preferably, χl and X- are identical and are butyl groups, in particular t-butyl groups. Preferably, Y is oxygen. Preferably Z and Z*^ are identical, in particular OR in which R is H, or a straight or branched Cj.galkyl group. More preferably, Z-* and 7?- are identical OR groups in which R is Cj.galkyl, in particular methyl, ethyl or j-propyl. Preferably, G is OH. Suitable bioprecursors of the group OH as defined for G include, for example, OR 3 groups where R 3 is a straight or branched Cj-Cg alkyl group, a perfluorinated Cj-C6alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, suitable bioprecursors can also be a R 3 -C(O)O- group, a R 3 O-C(O)O- group, a R 3 NH-C(O)O- group, a R 3 C(O)OCH2θ- group, a R -SO2O- group where R 3 is defined as above. Preferably, D is A-C(O)-B, A-CH(OH)-B, A-CH 2 -B, (CH 2 ) t -(CH=CH) n -(CH2)t or S-(CH2) t , where - A is (CH 2 ) t , (CH=CH) n -CH-=CX 3 , (CH 2 ) r CHX 3 , S-(CH 2 ) t -(CH=CH) n , S-CX 4 X 5 , (CH=CH) n -CH=CH-C(O)-CHX , (CH2)p-CH=CH-C(O)-CHX 3 , (CH 2 ) t -C(O)-CHX 3 , S-(CH 2 ) r (CH=CH) n -C(O)-CHX 3 , S-CX 4 X 5 -C(O)-CHX 3 , (CH=CH) n -CH=CH-CH(OH)-CHX , (CH2)p-CH=CH-CH(OH)-CHX 3 , (CH 2 )t-CH(OH)-CHX 3 , S-(CH2) t -(CH=CH) n -CH(OH)-CHX 3 , S-CX^-CHCOH^CHX 3 , where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3, - X 3 is H, a straight or branched alkyl Cι~C6 group, a substituted or unsubstituted phenyl group, - X 4 , X-5 identical or different are H, a straight or branched C1-C4 alkyl group, - B is CH2, CH-X 6 , X 6 -C-X 7 , where X 6 and X 7 identical or different are halogen atoms (F,C1, Br), straight or branched C1-C6 alkyl groups, a substituted or unsubstituted phenyl group; when A is (CH 2 ) t , (CH=CH) n -CH=CX 3 , (CH 2 ) t -CHX 3 , S-(CH 2 ) r (CH=CH) n , S-CX 4 χ5, then B is also CH=CH-(CH 2 ) p , CH=CH-CHχ6, CH=CH-Cχ6χ 7 , where p and X^, X 7 are defined as above. Preferably, D can also be A'-CH(O-CO-X 8 )-B' where A' is (CH 2 ) t , (CH=CH) n -CH=CX 3 , (CH 2 ) t -CHX 3 , S-(CH 2 ) r (CH=CH) n , S-CX 4 χ5, B' is CH 2 , CH-X6, χ6_C-X 7 , CH=CH-(CH 2 )p, CH=CH-CHχ6, CH=CH-Cχ6χ 7 where t, n, p, X 3 , X 4 , X-5, X~ and X 7 are as described above, and X- is a saturated or unsaturated Cj-Cgalkyl or alkenyl chain. Suitable salts included within the scope of formula (I) include, for example, corresponding salts of the group OR (in _-.-fZ?-), for example salts formed with alkali metal atoms such as sodium or potassium. PROCESSES FOR PREPARING COMPOUNDS OF FORMULA m The present invention also relates to the processes used for preparing substituted phosphonates (I). D is A-C(0)-B A is (CH 2 ) t , (CH=CH) n -CH=CX 3 , (CH 2 ) t -CHX 3 , S(CH 2 ) t -(CH=CH) n or S-CX 4 X 5 B is CH 2 , CH-X6 or C-X 6 X 7 The procedure described in Fig. 1 p. 10 consists in reacting the commercially available alkylphosphonate HI with a suitable base such as n-butyllithium or lithium diisopropylamide. The lithium anion of compound HI thus formed is then reacted in situ with the appropriate ester II to give the substituted phosphonates (I). The reaction is carried out in an ether solvent such as dimethoxyethane or tetrahydrofuran (THF), preferably in THF, at a temperature between -78°C and room temperature (25°C). A second procedure described in Fig 2 p. 11 consists in condensing the unsaturated aldehyde IV with the starting compound ketophosphonate V using titanium tetrachloride and N-methyl morpholine as condensation agents. The reaction is carried out in an ether solvent such as tetrahydrofuran, dioxane or dimethoxyethane, preferably THF, at a temperature between -30°C and the boiling point of the solvent (66°C in the case of THF). A compound of formula (I) where A is (CH=CH) n -CH=CX 3 is obtained. Compounds of formula (I) where A is (CH2) f CHX 3 can be prepared by reacting the starting compound ketophosphonate V with an excess of a base or combination of bases. The bases are sodium hydride, sodium alkoxides, n-butyl lithium or lithium dϋsopropylamide. The anion of ketophosphonate V thus formed is then reacted with the halide VI, where Hal = Br or Cl. The reaction is carried out in tetrahydrofuran, dimethoxyethane, dioxane, benzene or toluene. The temperature of the reaction varies between 0°C and the boiling point of the solvent. Examples 1, 2, 3 and 4 further illustrate the experimental aspects of the process described in Fig 2. Concerning condensation reactions, in the case where B is a CH2 group, i.e. when the carbon alpha to the phosphonate functional group has two protons, in addition to the main reaction product formed by monocondensation at the gamma position, a side product is also formed by double condensation with the dialkyl phenol groups at the alpha and gamma positions (see ex 1 and 2). In the case where B = CHX^ or χ6- C-X 7 , e.g. when two protons are not available at the alpha position, the compound formed by monocondensation at the gamma position is the sole reaction product (see ex 4 and 10). Likewise, when the alpha position is completely unsubstituted (B=CH2), in addition to the main reaction compound formed by monoaddition, these is also formed a side product occurring by double additions at the alpha and gamma positions (see ex 3). A is (CH=CH) n -CH=CH-C(O)-CHX 3 , (CH 2 ) p -CH=CH-C(O)-CHX 3 , (CH 2 ) t -C(O)-CHX 3 , S(CH 2 ) r (CH=CH) n -C(O)-CHX 3 or S-CX 4 X 5 -C(O)-CHX 3 B is CH 2 , CH-χ6 or C-X 6 X 7 The process described in Fig. 3 p. 12 consists in condensing an ester of formula VII with the dianion of ketophosphonate V at the gamma position. The dianion is generated by stepwise reaction of V with an equivalent of sodium hydride and an excess of a stronger base, e.g. n-butyl lithium or lithium diisopropylamide (LDA) in tetrahydrofuran at a temperature between -30° and 30°C. The excess of dianion is then reacted with the ester VII at a temperature between -70° and 30°C to yield the ketophosphonate (I) according to Fig. 3. Compounds (I) which possess two ketone groups in their structures may in solution be in tautomeric equilibrium with enol forms. The diketone and enol forms of compounds (I) are integral part of this invention. A is (CH 2 ) t , (CH=CH) n -CH=CX 3 , (CH 2 ) r CHX 3 or S(CH 2 ) r (CH=CH) n or S-CX 4 X 5 B is CH=CH-CX 6 X 7 or CH=CH-(CH 2 ) p The procedure for preparing compounds of formula (I) where D is A-C(O)-B, where A is (CH 2 ) t , (CH=CH) n -CH=CX 3 , (CH 2 ) r CHX 3 , S(CH 2 )t-(CH=CH) n or S-CX 4 X 5 , B is CH=CH-CX 6 X 7 or CH=CH-(CH 2 ) p consists in reacting an aldehyde of formula Villa or Vmb Y i Y J 6 _ _.7' I "I/ ^ ΠHΓ — trx.. \ ■_ "_ / OHC — CX X— P 2 OHC — ( CH 2 ) p _ p > ^ 2 Z z Villa VHIb with a phosphorus reagent which may be a phosphonate compound of formula IX or a phosphonium salt of formula X: 1 X G— <v / > ■ — A C CH 2 — P0 3 (Alkyl) 2 2 X IX The reaction is carried out in an ether solvent, such as dimethoxyethane or tetrahydrofuran in presence of a base such as sodium hydride or lithium diisopropylamine. D is A-CH(OH)-B The ketophosphonates of formula (I) previously described can be reduced to the corresponding hydroxyphosphonate derivatives. The reduction can be carried out with complex hydride reagents such as sodium borohydride, lithium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium trimethoxyborohydride, sodium cyanoborohydride. Suitable solvents include ether, tetrahydrofuran, toluene, methanol, ethanol, isopropanol. Prefered reduction conditions are sodium borohydride in methanol at a temperature between -20°C and 65°C. D is A'-CH(O-CO-X 8 )-B' The above-mentioned hydroxyphosphonates can be esterified to the corresponding acyloxy-phosphonate derivatives by employing known procedures. Suitable reaction conditions involve heating the hydroxyphosphonates with an appropriate acid anhydride (X~-CO)~P or an appropriate acid chloride X^-CO-Cl in presence of a tertiary amine, eg. triethyl amine or pyridine. The reaction temperature can range between 0°C to the boiling point of the acylating agent. D is A-CH 2 -B, (CH 2 )t-(CH=CH) n -(CH 2 )t, S-(CH 2 ) t The ketophosphonates (I) can be reduced to the corresponding alkylphosphonates and alkenylphosphonates by reduction of the p-toluenesulfonylhydrazone derivatives with sodium borohydride, sodium cyanoborohydride or catechol borane. Phosphonic acids of structure (I) where Zl=Z*^=OH can be prepared from the corresponding phosphonate esters by reaction with bromotrimethyl silane to produce bis (trimethylsilyl) phosphonates which are reacted in situ with water or methanol. The starting compounds alkylphosphonates HI are commercially available. The starting compounds ketophosphonates V are prepared according to known literature methods: E. J. Corey and G. T. Kwiatkowski, J. Am. Chem. Soc.2Q, p. 6816-6821 (1968) and F. Mathey and P. Savignac, Tetrahedron 24, P- 649-654 (1978). X CH 2 — v L = Cl or OEt M = Li or Cu The structures of new compounds of formula (I) are determined by infrared (IR), mass (MS) and nuclear magnetic resonance (NMR) spectroscopies. The purity of the compounds is verified by elemental analysis and standard chromatographic methods: thin layer chromatography, gas liquid chromatography or high performance liquid chromatography. The abbreviations used in this patent application are as follows: In the tables n- is normal, i- is iso-, sec is secondary-, t is tertiary. In the NMR spectra, s is singlet, d is doublet, t is triplet, m is multiplet. The temperatures are measured in degree Celsius and the melting points are uncorrected. The present invention will be further described by the examples 1 to 22 which are typical of the synthetic procedures used. FIR 1: SYNTHETIC FRQCESS II III (I) A = (CH 2 ) t , (CH=CH) n -CH=C-X 3 , (CH 2 ) t -CHX 3 , S-(CH 2 ) t ~(CH-CH) n or S-CX 4 X 5 B CH 6 V 7 0' CH-X υ or C-X υ X FIG 2 SYNTHETIC PROCESS ( I ) A = (CH=CH) -CH=CX FIG 3: SYNTHETIC PROCESS A = E -CHX where E is (CH=CH) n -CH=CH , (CH 2 ) p -CH=CH , (CH 2 ) t , S (CH 2 ) fc - (CH=CH) n or S-CX 4 X 5 Examnle 1 Dimethyl 1.5-bisr3.5-di-tert-butvl-4-hvdroxvphenvlV3-oxo- 1.4-pentadien-2-vl phosphonate and Dimethyl 4-f3.5-di-tert-hutvl-4-hvdroxvphenvlV2-oxo-3-buten-l -vl phosphonate Titanium tetrachloride (114.5g, 0.6 mol) was added dropwise with stirring to 300 ml of dry tetrahydrofuran (THF) kept under nitrogen at -20°C. Solid 3,5-di-tert-butyl-4- hydroxy benzaldehyde (58.7g, 0.25 mol) was added, followed by 200 ml THF then dimethyl 2-oxopropylphosphonate (50 g, 0.3 mol) was added. Finally N-methyl morpholine (121.7g, 1.2 mol) was introduced slowly and the reaction mixture was stirred at room temperature for 1 h. Cold water (200 ml) was introduced and the mixture was extracted with 1000 ml diethyl ether. The ether fraction was washed with water until neutral pH, dried over magnesium sulfate and evaporated in vacuo. Purification was carried out by chromatography on silica gel using a 98/2 chloroform methanol mixture. The first compound (5.5 g, 4%) to elute from the column was identified as dimethyl 1 ,5-bis(3,5-di-tert-butyl-4-hydroxyphenyl)-3-oxo- 1 ,4-pentadien-2-yl phosphonate. C35H51O6P heor. Found mp = 190-191°C. IR (KBr): 3620cm "1 : OH, 1610: C=O, 1580: C=C, 1430and 1420: t-Bu, 1240: P=O, 1020: P-O-C MS: m/e=599:M++1,598: M + ,488:M+-H-PO3Me 2 , 367 (100%) NMR (CDCI3) δ = 7.75 (d, J = 26 Hz, IH): Ph-CH=C-P 7.57 (d, J = 16 Hz, IH): Ph-CH=CH- 7.3 and 7.23 (2 s, 2H each): arom. H 6.60 (d, J= 16Hz, IH): Ph-CH=CH 5.55 and 5.51 (2s, IH each): OH 3.82 (d, J = 11Hz, 6H): P-O-CH3 1.40 and 1.34 (2 s, 18H each): t-C^ The second compound (36 g, 38 % yield) was identified by IR, MS and NMR as dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1-yl phosphonate t-Bu mp = 107-109° (ligroin, 80-95 fraction) IR (KBr): 3420 cm" 1 : OH, 1650: C=O, 1590: C=C, 1420: t-Bu, 1260: P=O and 1030: P-O-C MS (m/e): 382 M+, 367: M+-Me, 272: M + -HPO3Me 2 , 259:M + -CH 2 PO3Me2, 151: M + -CO-CH 2 -PO3Me 2 Example 2 Diethvl 1 ■5-hisf3.5-di-tert-hutvl-4-hvdroxvphenvn-3-oxo-l .4-pentadien-2-vl phosphonate and Diethvl 4-f .5-di-tert-butvl-4-hvdroxvphenvn-2-oxo-3-buten- 1 -vl phosphonate Titanium tetrachloride (137J g, 0.72 mol) was added dropwise to 300 ml dry THF at -15°C. 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (70.4 g, 0.30 mol) was added followed by diethyl 2-oxopropylphosphonate (70 g, 0.36 mol). N-methyl morpholine (145.8 g, 1.44 mol) was introduced and the reaction mixture was stirred at room temperature for 2 h. Work up was carried out by addition of 200 ml water and 800 ml diethyl ether. The ether phase was washed with water to neutral pH, dried over MgSO4 and evaporated. The residue was chromatographed on silicagel using 98/2 CHCl3 MeOH as eluent. The first product (15 g, 8% yield) to elute was identified as diethyl l,5-bis(3,5-di- tert-butyl-4-hydroxyphenyl)-3-oxo- 1 ,4-pentadien-2-yl phosphonate. C37H55O6P Theor. % C 70.90 % H 8.84 % P 4.94 Found % C 71.18 % H 8.67 % P 4.75 mp = 174-175°C IR: (KBr): 3620 cm' 1 : OH, 1640: C=O, 1585: C=C, 1430 and 1415: t-Bu, 1230: P=O and 1030: P-O-C MS: m/e = 626: M+ 488: M+-HPO 3 Et 2 , 395 (100%) NMR (CDCI3) δ = 7.7 (d, J = 26 Hz, 2H): Ph-CH=C-P 7.59 (d, J = 16Hz, 2H): Ph-CH=CH 7.30 and 7.25 (2s, 2H each): arom. H 6.63 (d, J = 16 Hz, 2H): Ph-CH=CH 5.54 and 5.48 (2s, IH each): OH 4.18 (quint, J = 7Hz, 4H): P-O-CH2-CH3 1.40 and 1.34 (2s, 18H each): t-C i9 1.34 (t, J= 7 Hz, 6H): P-O-CH2-CH3 The second product was identified as diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) 2-oxo-3-buten-l-yl phosphonate (44 g, 36% yield) t-Bu mp = 110-111°C (recrystallized from ligroin 80-95 fraction). IR (KBr): 3620 cm" 1 : OH, 1680:C=O, 1590: C=C, 1430 and 1415: tBu, 1240: P=O and 1230: P-O-C MS (m/e): 411: M+l, 410: M+, 272: M + -H-PO 3 Et 2 , 259: M + -CH 2 PO Et2, 57 (100%): tBu + NMR (CDCI3) δ = 7.61 (d, J = 16 Hz, IH): Ph-CH=CH 7.40 (s, 2H): arom. H 6.74 (d, J = 16Hz, IH): Ph-CH=CH 5.6 (s, IH): OH 4.16 (m, 4H): P-O-CH2-CH3 3.33 (d, J = 23 Hz, 2H): Qfe-P 1.34 (t, J = 7Hz, 6H): P-O-CH 2 -CH3 Sodium hydride (1.45 g of a 60% dispersion in mineral oil, 36.25 mmol) was suspended under nitrogen in hexane, this latter was pipetted out and replaced by 60 ml dry THF. Diethyl 2-oxopropylphosphonate (7.0 g, 36 mmol) was introduced. The mixture was stirred at room temperature for 30 min then was cooled to 0° C then n- butyl lithium (37.5 ml of a 1.6 M solution, 60 mmol) was added. Finally a solution of 3,5-di-tert-butyl-4-hydroxybenzyl bromide (9.0 g, 30J mmol) in 40 ml THF was added and the reaction mixture was stiιτed at room temperature overnight. Work-up was carried out by partition between 150 ml 15% HC1 and two fractions of 150 ml ether. The ether phase was washed with sodium bicarbonate and saturated sodium chloride to neutral pH. After drying and solvent evaporation, the crude mixture was purified by column chromatography (Siθ2, 8/2 CHCi AcOEt). The first compound (1.5 g, 8% yield) to elute was diethyl l,5-bis(3,5-di-tert-butyl-4- hydroxy-phenyl)-3-oxo-2-pentyl phosphonate, mp = 60-61°C. IR (KBr): 3620 cm" 1 : OH, 1710: C=O, 1430: t-Bu, 1230: P=O and 1010: P-O-C MS:m/e= 630: M + , 493: M + -HPO3Et2 NMR (CDCI3) δ = 6.89 (2s, 2H each): arom. H 5.09 and 5.03 (2s): OH 4.1 (m, 4H): P-O-CH2-CH3 3.5 and 3.25 (2m, 2H): Ph-CH2"CH-P 3.04 (txd, IH): Ph-CH 2 -CH(P)-CO 2.9 - 2.4 (2m, 4H): Ph-CH2-CH2"CO- 1J4 and 1.39 (2s, 18H each): t-C H9 1.32 (2t, J=7Hz, 6H): P-O-CH 2 -CH3_ The second compound was diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-l- butyl phosphonate: 2.2 g (18% yield) of an oil was obtained which slowly solidified upon standing. - -CH, — : P0 3 Et t-Bu IR (film): 3620 cm" 1 : OH, 1710: C=O, 1430: t-Bu, 1250: P=O, 1010: P-O-C MS m/e= 412: M+, 274: M-HPO 3 Et 2 NMR : (CDCI3) δ = 6.98 (s, 2H): arom. H 5J (s, IH): OH 4J4 (m, 4H): P-O-CH2CH3 3.05 (d, J=25Hz, 2H): CH 2 -P 2.94 (m, 2H): Ph-CH2-CH 2.83 (m, 2H): Ph-CH 2 -CH2 1.42 (s, 18H): t-C H 9 1.32 (t, J=7Hz, 6H): P-O-CH 2 -CH3 Examnle 4 Diethvl 4-f3.5-di-tert-butvl-4-hvdroxvρhenvn-l J -dimethvl-2-oxo-3-huten-l-vl- phosphonate Diethyl l,l-dimethyl-2-oxo-propylphosphonate (bp = 6070.2 mbar) was synthesized according to V. Roussis and D.F. Wiemer, J. Org. Chem.54, p. 627-631 (1989). To 20 ml dry THF kept at 0°C were added sequentially ΗCI4 (1.72 g, 9 mmol), 3,5- di-tert-butyl-4-hydroxybenzaldehyde (0.9 g, 3.8 mmol), diethyl lJ-dimethyl-2- oxopropylphosphonate (1.0 g, 4.5 mmol), N-methyl morpholine (1.82 g, 18 mmol) then the reaction mixture was stirred for 1 h at room temperature. Work up carried out in the usual manner gave an oil which was purified by column chromatography (SiO , 8/2 CHCI3/ACOE . An amount of 1.1 g (68% yield) of the title compound was obtained. Mp = 91-92°C (petroleum ether 40-60). IR: (KBr): 3440 cm" 1 : OH, 1670: C=O, 1590: C=C, 1430 and 1410: t-Bu, 1210: P=O and 1030: P-O-C MS: m/e= 439: M + + 1, 259: M+-C(CH3) 2 -PO 3 Et , 57 (100%): tBu Examnle 5 Diethvl 4-(3.5-di-tert-butvl-4-hvdroxvDhenvlV3-methvl-2-oxo-3-buten- 1 -vl phosphonate t-Bu Diethyl 2-oxobutylphosphonate (bp = 9070.6 mbar) was prepared according to F. Mathey and P. Savignac, Tetrahedron 24, P- 649-654 (1978). To 20 ml dry THF kept at 0°C were added successively ΗCI4 C 1 - 82 g, 9 - 6 mmol), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.94 g, 4 mmol), diethyl 2- oxobutylphosphonate (1 g, 4.8 mmol) and N-methyl morpholine (1.86 g, 18.4 mmol). The reaction mixture was stirred at room temperature for 30 min then was heated to reflux for 1 h. After the usual work-up and extraction the crude reaction mixture was purified by column chromatography (SiO 2 , 8/2 CHCi AcOEt). A small amount of unreacted benzaldehyde was first collected then 0.35 g (21%) of the title compound was obtained. Mp = 97-101°C (petroleum ether 40-60). IR (KBr): 3400 cm' 1 : OH, 1680: C=O, 1610 and 1590: C=C, 1440: t-Bu, 1250: P=O and 1020: PO-C MS: m/e = 424: M + , 409: M + -CH 3 , 367: M+-tBu, 286: M+-HPO3Et 2 , 57 (100%): tBu + NMR (CDCI3): δ = 7.56 (s, IH): Ph-CH=C 7.33 (s, 2H): arom. H 5.5 (s, IH): OH 4J6 (m, 4H): P-O-CH -CH 3.51 (d, J=22Hz, 2H): CH -P 2J (s, 3H): CH3 1.46 (s, 18H): t-C4H9 1.32 (t, J= 7Hz, 6H): P-O-CH 2 -CH3 C23H 37 O 5 P Calc. % C 65.07 % H 8.79 % P 7.30 Found % C 65.35 % H 8.58 % P 7.51 Example 6 Dimethyl 4-(3.5-di-tert-butyl-4-hydroxyphenyl V3-(n-butylV2-oxo-3-buten- 1 -yl phosphonate t-Bu A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (3.65 g, 15 mmol), dimethyl 2-oxoheptylphosphonate (4.0 g, 18 mmol), ΗCI4 (6.84 g, 36 mmol) and N-methyl moipholine (7.27 g, 72 mmol) in 80 ml dry THF was refluxed as described in example 7. Purification by column chromatography (Siθ2, 8/2 CHCi AcOEt) gave 1.2 g (20% yield) of the title compound. Mp = 82-85° (petroleum ether 40-60) MS: m/e 439 M++ 1, 438 M+, 381 M+-C4H 9 , 57 (100%): tBu NMR (CDCI3) δ = 7.48 (s, IH): Ph-CH=C(C H 9 ) 7.32 (s, 2H): arom. H 5.5 (s, IH): OH 3.81 (d, J = 11Hz, 6H): P-O-CH3 3.52 (d, J = 22Hz, 2H): CH2-P 2.57 (m, 2H): CH2-C3H7 1.5-1.4 (m, 4H) CH 2 -(CH2)2-CH 3 1.5 (s, 18H): t-C4H9 0.94 (t, J = 7Hz, 3H): (CH 2 )3-CH3 Examnle 7 Diethyl 4-(3.5-di-tert-hutvl-4-hvdroxvDhenvn-2-oxo-3-Dhenvl-3-buten- 1 -vl phosphonate The procedure described in example 5 was employed, using as the phosphonate reagent diethyl 2-oxo-3-phenylpropylphosphonate (bp= 15070.5 mbar). The title compound was isolated by column chromatography under die usual conditions (Siθ2, 8/2 CHCi AcOEt) at ca 18% yield. mp=139-143°C IR (KBr): 3500: OH, 1640: C=O, 1610 and 1590: C=C, 1430: t-Bu, 1230: P=O, 1020: P-O-C. MS: m/e=486 (100%) M + , 348: M + -HPO3Et 2 , 335: M + -CH 2 PO3Et 2 NMR: (CDCI3) δ = 7.70 (s, IH): Ph-CH=C 7.45 - 7.25 (m, 5H): CgHs 6.97 (s, 2H): arom. H 5.46 (s, IH): OH 4.15 (m, 4H): P-O-CH2-CH3 3.33 (d, J=22Hz, 2H): Qfc-P 1.32 (t, J=7Hz, 6H): P-O-CH 2 -CH3 1.23 (s, 18H): C4H9 C28H39O5P Calc. % C 69.11 % H 8.08 % P 6.37 Found % C 69.37 % H 8J 1 % P 6.61 Example 8 ' Diethvl 4-f -5-di-tert-butvl-4-hvdroxvphen vlV 1 -methvl-2-oxo-3-huten- 1 -vl phosphonate Diethyl l-methyl-2-oxopropylphosphonate was prepared according to Mati ey and Savignac as cited as example 5. A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (7J9 g, 29 mmol), diethyl 1- methyl-2-oxopropylphosphonate (8.20 g, 35 mmol), ΗCI4 (13.47 g, 71 mmol), N- methyl morpholine (14.34 g, 140 mmol) in 150 ml dry THF was reacted at room temperature for 1 h, then at reflux temperature for 18 h. After work up, column chromatography (SiO 2 , 8/2 CHCi AcOEt) gave 4.7 g (38%) of the title compound. mp=92-94°C NMR (CDCI3) δ = 7.63 (d, J = 16Hz, IH): Ph-CH=CH 7.42 (s, 2H): arom. H 6.87 (d, J = 16Hz, IH): Ph-CH=CH 5.6 (s, IH): OH 4J5 (m, 4H): P-O-CH2-CH3 3.53 and 3.46 (two q, J = 24Hz and 7Hz, IH): CH-P 1.50-1.43 (two d, J = 7Hz): CH-(P)-CH3 1.46 (s, 18H): C4H9 1.32 (two t, J = 7Hz): P-O-CH 2 CH3 Example 9 Dimethyl 4-(3.5-di-tert-butyl-4-hydroxyphenyl')-2-oxo-3-buten- 1 -yl phosphonate Under nitrogen atmosphere dimethyl methylphosphonate (3J7 g, 25.6 mmol) was added at -60° to a solution of n-butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 15 ml anhydrous THF. The reaction mixture was stirred at -50° for 30 min to allow for complete formation of the lithium anion (slight turbidity). The mixture was again cooled to -60° and a solution of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) in 20 ml dry THF was added. The resulting orange-colored mixture was left to stir at room temperature (25°C) for 18 h. Hydrolysis was carried out by adding 10 ml of a 10% HCl solution and die product was extracted into ether. After drying over MgSO4, ether was evaporated to yield a yellow solid. Recrystallization in 40 - 60 petroleum ether gave 3.0 g (92% yield) of dimethyl 4-(3,5-di-tert-butyl-4- hydroxyphenyl)-2-oxo-3-buten-l-yl phosphonate. mp=107-109°C The tide compound can also be obtained by using as d e bases a mixture of n-BuLi and LDA (lithium dϋsopropylamide). To a solution of n-butyllithium (16ml of a 1.6 M solution, 25.6 mmol) in 20 ml dry THF was added at -60°C diisopropyl amine (0.86 g, 8.5 mmol). The resulting mixture was stirred at -40° for 15min, then dimethyl memylphosphonate (2J1 g, 17 mmol) was added. After 15 min, ethyl 3,5-di-tert-butyl- 4-hydroxycinnamate (2.6 g, 8.5 mmol) was added and die reaction mixture was stirred at room temperature (25°C) for 15 h. Work up by addition of 10% HCl and extraction into ether gave 3J0 g (95%) of dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo- 3-buten-l-yl phosphonate. mp=107-109°C The compound prepared by either of these two variant processes has spectroscopic data identical to those of the same product described in example 1. C 2 oH 31 O 5 P Theor. %C 62.81 %H 8J7 %P 8J0 Found %C 62.56 %H 8.21 %P 8.24 Example 1ft Diethvl 6-(3.5-di-tert-butvl-4-hvdroxvphenvn-lJ-dimethvl-2-oxo-3.5-hexadien-l-vl phosphonate To 15 ml dry THF kept at 0° were added ΗCI4 (1.23 g, 6.47 mmol), 3,5-di-tert-butyl- 4-hydroxy cinnamaldehyde (0.7 g, 2.67 mmol), diediyl lJ-dimethyl-2- oxopropylphosphonate (0.72 g, 3.24 mmol) and N-methylmorpholine (1.31 g, 12.97 mmol). The reaction mixture was stirred for 1 h at 20°C dien 1 h at 30°C. Work-up gave a dark oil which was purified by column chromatography (SiO 2 , 8/2 CHCi AcOEt). 650 mg (52%) of yellow crystals were obtained, mp = 130-133°C. NMR (CDCI3) δ = 7.40 (d x d, J = 11 and 15Hz, IH): Ph-CH=CH-CH=CH 7.2 (s, 2H): arom. H 6.87 and 6.85 (2 d, J = 15Hz, 2H): Ph-CH=CH-CH=CH 6.75 (d x d, J = 11.5 and 16Hz, IH): Ph-CH=CH-CH=CH 5.4 (s, IH): OH 4.1 (m, 4H): P-O-CH2-CH3 1.40 (d, J = 16Hz, 6 H): C(CH3)2 1.39 (s, 18H): t-C4H 9 1.24 (t, J = 7Hz, 6 H): P-O-CH 2 -CH3 MS: m/e=464: M + , 326: M+- HPO3Et 2 , 285 (100%): M+- CMe 2 -PO3Et 2 C26H41O5P Calc. % C 67.22 % H 8.90 % P 6.67 Found % C 66.68 % H 8.56 % P 6.21 Example 11 Dimethyl 4-f3.5-di-tert-hutvl-4-hvdroxvphenvlV2-oxo-l -butvl phosphonate t-Bu HO— - . Λ— CH 2 -CH 2 C CH 2 — P0 3 Me 2 t-Bu A solution of dimethyl litiiiomethylphosphonate was prepared under nitrogen by adding dimethyl memylphosphonate (3.2 g, 25.6 mmol) to a solution of n- butyllithium (16 ml of a 1.6 M solution in hexane, 25.6 mmol) in 15 ml dry THF at - 60°C. To this solution was added at -60° a solution of etiiyl 3,5-di-tert-butyl-4- hydroxyhydrocinnamate (2.6 g, 8.5 mmol) in 20ml THF. The resulting solution was stirred at -60° for 30 min and tiien was allowed to reach room temperature (25°C) overnight. 25 ml 10% HCl was added and d e mixture was extracted into ether. The residue of the ether phase was purified by column chromatography (Siθ2, 8/2 CHCi AcOEt) to yield a white solid. Recrystallization in petroleum ether gave 2J g (64% yield) of the tide compound. mp=78-79°C MS: m/e=384: M + , 284: M + -HPO 3 Me 2 , 57 (100%): tBu NMR (CDCI3) δ = 6.98 (s, 2H): arom. H 5.06 (s, IH): OH 3.75 (d, J = 11.5Hz, 6H): P-O-CH3 3.08 (d, J = 22.5Hz, 2H): CH2-P 2.90 (m, 2H): Ph-CH2"CH 2 2.81 (m, 2H): Ph-CH 2 -CH2 1.41 (s, 18H): t-C4H9 Example 12 ' Diethvl 6-f 3.5-di-tert-hutvl-4-hvdroxvphenvn-2.4-dioxo-5-hexen- 1 -vl phosphonate t-Bu Diethyl 2-oxopropylphosphonate (3.4 g, 17 mmol) was added at room temperature under nitrogen to a suspension of sodium hydride (0.82 g of a 60% dispension, 20 mmol) in 35 ml dry THF. The mixture was stirred at room temperature for 60 min, then diisopropylamine (1.71 g, 17 mmol) was added at 0°, followed by n- butyllithium (21 ml of a 1.6 M solution, 34 mmol). After 30 min at 0°, the mixture was cooled to -60° and a solution of etiiyl 3,5-di-tert-butyl-4-hydroxycinnamate (2.6 g, 8.5 mmol) in 25 ml THF was induced dropwise. The resulting mixture was stirred at 0° for 2 h, at 25°C for 1 h, hydrolyzed with 60 ml H2O whereupon it separated into two phases. The aqueous phase was acidified witii 10% HCl and was extracted with two 100 ml portions of ether. The ether extracts were pooled witii the THF phase, dried and evaporated. The residue was purified by column chromatography (Siθ2, 8/2 CHCi AcOEt) to yield a viscous orange oil. Recrystallization in ligroin gave 2.25 g (60% yield) of the tide compound, mp=109- 110°C NMR (CDCI3) δ = 7.60 (d, J=16Hz, IH): Ph-CH=CH 7.37 (s, 2H): arom. H 6.35 (d, J= 16Hz, IH): Ph-CH=CH 5.83 (s, IH): CO-CH=C-OH 5.54 (s, IH): phenol OH 4J7 (m, 4H): P-O-CH2-CH3 3.02 (d, J = 22Hz, 2H): CH2-P 1.46 (s, 18H): t-C4H9 1.34 (t, J = 7Hz, 3H): P-O-CH2-CH3 MS: m/e 452 M + , 314 M+ - HPO3Et 2 , 57 (100%) tBu Example 13 Diethvl 6-f3.5-di-tert-butvI-4-hvdmxvphenvlV2.4-dioxo-l-hexvl phosphonate t-Bu Diethyl 2-oxopropylphosphonate (2.02 g, 10 mmol) was added at room temperature to sodium hydride (0.48 g of a 60% dispersion, 12 mmol) suspended in 30 ml THF. After 30 min the mixture was cooled to 0° and diisopropylamine (1.01 g, 10 mmol) and n-butyllithium (13 ml of a 1.6 M solution, 21 mmol) were added. After 30 min, the mixture was cooled to -60° and etiiyl 3,5-di-tert-butyl-4-hydroxy hydrocinnamate (1.6 g, 5.2 mmol) dissolved in 15 ml THF was added. The mixture was left to react at -60° for 15 min then at 0° for 2 h and 25°C for 1 h and was hydrolyzed with 10% HCl and extracted widi ether. Column chromatography (Siθ2, 8/2 CHCi AcOEt) gave 1.0 g (42%) of the tide compound as a colorless oil. NMR (CDCI3) δ = 6.98 (m, 2H): arom. H 5.70 (s, IH): CO-CH=C-OH 5.09 (s, IH): phenol OH 4J5 (m, 4H): P-O-CH2-CH3 2.92 (d, J = 22.5Hz, 2H): CH2-P 2.85 (m, 2H): Ph-CH2-CH 2 2.59 (m, 2H): Ph-CH 2 -CH2 1.43 (s, 18H): t-C4H9 1.33 (t, J = 7Hz, 6H): P-O-CH 2 -CH3 MS: 455 M+ +1, 454 M+, 436 M + -H 0, 57 (100%) tBu Example 14 Dimethyl 6-r3.5-di-tert-butvl-4-hvdroxvphenvlV2.4-dioxo-5-hexen- 1-vl phosphonate t-Bu The procedure described in example 12 was followed using dimethyl 2-oxo- propylphosphonate to give the tide compound at 79% yield, yellow solid wid mp = 145-146°C. Example 15 2-r4-(3.5-di-tert-hutvl-4-hvdroxvphenvlV2-oxo-3-buten- 1 -vll C2-OXO- 1.3.2-dioxaphosphorinan'> Under nitrogen atmosphere, 2-methyl-2-oxo-l,3,2-dioxaphosphorinan (2.62g, 19.2 mmol) dissolved in THF/dioxane (30ml each) was added to an equimolar amount of n-butyllithium in 35ml THF at -60°C. The mixture was stirred at -60°C for 30 min then a solution of ethyl 3,5-di-tert-butyl-4-hydroxycinnamate (2g, 6.4 mmol) in 20ml THF was added. The resulting mixture was stirred at -60°C for 30 min and left to attain room temperature (25°C) over 16 h. After the usual work up, column chromatography (silicagel, 98/2 CΑCl^ ΛeOH) gave 0.76g of the tide compound (30%). mp = 158-161°C MS: m/e = 394 M + , 57 (100%): tBu NMR (CDCI3): * δ = 7.65 (d, J= 16Hz, IH): Ph-CH=CH 7.42 (s, 2H): arom. H 6.74 ( d, J = 16Hz, IH): Ph-CH=CH 5.7 (s, IH): OH 4.5-4.4 (large m, 2H): P-O-CH2 3.45 (d, J = 22Hz): CH2-P 2.1 and 2.0 (2m, 2H): P-O-CH 2 -CH2 1.45 (s, 18H): t-C4H 9 Example 16 Diedivl 4-(3.5-di-tert-hutvl-4-hvdroxv > )-4-oxo-2-buten- 1 -vl phosphonate To a suspension of 730mg 60% sodium hydride (18 mmol) in 20ml THF was added 3.0g (8.4 mmol) of dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-l ethylphosphonate in 25ml THF. The mixture was stirred for 30 min then it was cooled to 0° and 3.1 g (18 mmol) dietiiyl formylmethylphosphonate was added. The resulting mixture was stirred at 0°C for 1 h then at 25°C for 16h, partitioned into ether and water and die organic phase was evaporated. Purification by means of column chromatography (silicagel 98/2 dichloromethane/methyl t-butyl etiier) gave 550mg (16%) of the tide compound, mp = 68-70°C MS=m/e: 410 M + , 395: M+-CH 3 , 272: M + -HPO 3 Et2, 233 (100%) M+-CH=CH-CH2PO3Et2 NMR: CDCI3 δ = 7.83 (m, 2H): arom. H, 7.1 (dd, J=15 and 4.5Hz, IH), Ph-CO-CH=CH 6.9 (m, 2H): Ph-CO-CH=CH 5.7 (s, IH): OH 4.15 (m, 4H): P-O-CH2-CH3 2.86 (dd, J=23 and 7Hz): CH2- 1.48 (s, 18H): t-C 4 H 9 1.34 (t, 6H): P-O-CH 2 -CH3 Example 17 Dimethyl 4-(3.5-di-tert-butvl-4-hvdroxv phenvn-2-hvdroxv-3-huten-l -vl phosphonate t-Bu To 100 ml of a methanol solution of dimetiiyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)- 2-oxo-3-buten-l-yl phosphonate (1.9g, 5 mmol) cooled to -10°C were added 0.75g sodium borohydride. The reacting mixture was stirred at -10°C for 1 h then at room temperature (25°C) for 2 h. Work up was carried out by addition of 100ml ether and 60ml sodium bicarbonate solution. The ether phase was washed with brine, dried over MgSO4 and evaporated to yield 1.6g (85%) of die tide compound. mp = 122-123°C MS (m/e)= 384:M + , 366: M + -H 2 0, 256: M+-H 2 O-HPO Me2 NMR (CDCI3): δ= 7.21 (s, 2H): arom. H 6.59 (d, J = 16Hz, IH): Ph-CH=CH, 6.08 (dd, J = 16 and 6Hz, IH): Ph-CH=CH 5.26 (s, IH): OH (phenol) 4.7 (m, IH): CH-OH 3.78 (2xd, 6H): PO3 £2 3.4 (hump, IH): CH-OH 2.15 (distorted dd, 2H): CH 2 - p 1.44 (t, 18H): t-C H 9 Example 18 Dimethyl 4-G.5-di-tert-hutvl-4-hvdroxvphenvlV2-oxo-3-huten-l-vl thionophosphonate Under nitrogen atmosphere dimethyl mediylthionophosphonate (3.1 g, 25 mmol) was added at -60°C to a solution of n-butyllithium (16ml of a 1.6M solution, 25.6 mmol) in 50ml THF. The mixture was stirred at -60°C for 15 min then a solution of etiiyl 3,5-di-tert-butyl-4-hydroxy cinnamate (2.5g, 8.2 mmol) in 20 ml THF was added. The resulting mixture was stirred at -60°C for 30 min and at room temperature (25°C) for 2 h. After the usual hydrolysis and work up, the compound was purified by column chromatography (Siθ2, 9/1 CHCiyAcOEt) and recrystallization in CHCiypetroleum ether to yield 1.7g (52%) of a yellow solid, mp = 88-90°C MS: m/e = 398: M+, 259: M + -CH 2 P(S)(OMe) 2 , 125: P(S)(OMe) 2 , 57 (100%) NMR (CDCI3) δ= 7.60 (d, J = 16Hz, IH): Ph-CH=CH 7.42 (s, 2H): arom. H 6.75 (d, J = 16Hz, IH): Ph-CH=CH 5.6 (s, IH): OH 3.78 (d, J = MHz, 6H): P(S)-OCH3 3.56 (d, J = 20Hz, 2H): CH2-P 1.46 (s, 18H): t-C4H9 C20H31O4PS Theor. %C 60.28 %H 7.84 %P 7.77 %S 8.04 Found %C 60.58 %H 8.04 %P 8.05 %S 8.30 Example 19 Dimethyl 3-(3.5-di-tert-hutvl-4-hvdroxvphenvlthioV2-oxo-l-propvl phosphonate CH 2 C CH 2 — P0 3 Me 2 To a THF solution of dimethyl lithiomethylphosphonate (24.6 mmol) kept at -60°C was added a solution of ediyl 3,5-di-tert-butyl-4-hydroxyphenyl thioacetate (2g, 6.2 mmol) in 15ml THF. The resulting mixture was stirred at -60°C for 30 min and was allowed to reach room temrjerature (25°C) over 4 h. After addition of 15ml 10% HCl, the reaction mixture was partitioned between ether and water. The residue after evaporation of the organic phase was purified by column chromatography (Siθ2, 8/2 CHCiyAcOEt) and recrystallization in petroleum ether to give 0.95g of the tide compound (38%). mp = 63-65°C MS: m/e 402: M+, 251: M + -(CO-CH 2 -PO3Me 2 ), 57 NMR (CDCI3) δ = 7.21 (s, 2H): arom H 5.3 (s, IH): OH 3.75 (d, J = 11Hz, 6H): P-O-CH3 3.72 (s, 2H): S-CH2-CO 3.33 (d, J = 22Hz, 2H): CH2-P 1.41 (s, 18H): t-C4H9 Example 20 Dimet yl 3-(3.5-di-tert-butvl-4-hvdroxvphenvlthioV3.3-dimethvl-2-oxo- 1 -propvl phosphonate To 10ml of a THF solution of dimethyl lidiiomethylphosphonate (68.2 mmol) kept at -60°C was added a solution of etiiyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl-dιio-2- methylpropionate (6g 17.1 mmol) in 15ml THF. The resulting mixture was stirred at -60°C for 30 min and was allowed to reach room temperature (25°C) over 4 h. After addition of 15ml 10% HQ, the reaction mixture was partitioned between ether and water. The residue after evaporation of the organic phase was purified by column chromatography (Siθ2, 8/2 CHCiyAcOEt). Recrystallization in petroleum ether gave 4.16g of die tide compound (57%). mp = 105-106°C MS: m/e 430: M+, 279: M + -(CO-CH2-PO Me 2 ), 194 (100%), 57 NMR (CDCI3) δ = 7.15 (s, 2H): arom H 5.38 (s, IH): OH 3.80 (d, J = 11Hz, 6H): P-O-CH3 3.46 (d, J = 22Hz, 2H): CH2-P 1.41 (m, 24H):t-C4H9 + C(CH 3 ) 2 Example 21 ' Dimethyl 4-(3.5-di-tert-butvl-4-hvdroxvphenvtt- 1 ,3-butadien- 1 -vl phosphonate A mixture of dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) 2-hydroxy-3-buten-l- yl phosphonate (2.3g, 6 mmol) in 1.70ml acetic anhydride and 1.26ml triethylamine was stirred at 60°C for 3h. Following hydrolysis widi 10ml H 2 O, the reaction mixture was extracted with 20ml diediyl ether. The ether phase was extracted wid 10% HCl and dried over MgSO4. The residue after evaporation was purified by column chromatography to give l.Og (46%) of the tide compound. mp = 113-115°C MS : m/e: 366 M+, 351 M + -Me, 57 (tBu) NMR (CDC1 ) δ = 7.32-7.20 (m, 3H): arom H + CH=CH-CH=CH-P 6.82 (lH,d): -CH=CH-CH=CH-P 6.74-6.66 (IH, m) CH=CH-CH=CH-P 5.67 (IH, dd, J = 16.6 and 19.5Hz): CH=CH-CH=CH-P 3.75 (d, 6H): PO-CH3 1.46 (19H, s): t-C4H9 Example 22 ' Dimethyl 4-f 3.5-di-tert-hιιtyl-4-hvdroxvphenvn-2-r4-pentenovloxvV 1 -hutvl phosphonate To a mixture of acetyl-4-pentenoate (0.66g, 4.6 mmol) and triethylamine (0.24ml, 1.7 mmol) was added 0.50g (1.37 mmol) of dimethyl 4-(3,5-di-tert-butyl-4- 0 hydroxyphenyl)-2-hydroxy-l -butyl phosphonate. The reaction mixture was kept at 60°C for 6 h, cooled and extracted into diediyl etiier and water. The residue of die dried organic phase was purified by column chromatography (Siθ2, 7/3 CHCl3 Methyl-tert-butyl ether) to yield 0.4g of a colorless oil (62%). 5 MS: m/e: 468: M + , 368: M+- CH 2 =CH-CH 2 -COOH, 258: 368 - HPO 3 Me 2 NMR (CDCI3) δ = 6.94 (s, 2H): arom H 5.85 (m, IH): CH 2 =CIi-CH2-CH2-COO 0 5J8 (m, IH): Ph-CH 2 -CH 2 -CH-CH 2 -P 5.0 - 5J (m, 2H): CH2=CH-CH 2 -CH 2 -COO 5J5 (s, IH): OH (phenol) 3.72 (2xd, 6H): PO3MS2 2.55 (m, 2H): Ph-CH 2 -CH 2 -CH-CH2-P 5 2.41 (m, 4H): CH 2 =CH-CH2-CH2-COO- 1.43 (s, 18H): t-C 4 H 9 ont.) BIOLOGICAL ACTTvTITES A. Antinxidapt Activity 1) Iron induced peroxide formation in rat liver homogenate Wistar rats were eutiianasied by ether inhalation. The livers were dissected out and homogenised widi a potter homogeneiser in 4 volumes of phosphate buffer (4°C, pH 7.4). After centrifugation at 2000 m for 10 min the supernatant obtained was kept at 4°C. A mixture containing 0.2 ml of liver homogenate, 1.7 ml of phosphate buffer was incubated witii 0J ml of a 2mM FeSO4 solution to induce peroxide formation according to die method described by A. T. Quintanilha et al., Ann. N. Y. Acad. Sci., 22 , 32-47, 1982. Compounds to be tested for antioxidant activity were dissolved in DMSO or ethanol and added in a volume of 5 μl to the incubation mixture. Stock solution of die compounds were diluted sequentially to obtain final concentration of 0.5, 1, 2, 5 and 5 μM. Oxidation was performed at 37°C for 2 hours and was stopped by die addition of 20 μl of a 2% ethanolic solution of BHT. The generated peroxides measured as malondialdehyde formation were quantitated according to the method of Yagi ("Lipid Peroxides in Biology and Medicine" p. 223-242, 1982, Ed. K. Yagi, Academic Press Inc.) using die Thiobaibituric Acid Reaction and widi lJ,3,3,-tetramethoxypropane as standard. Results are given as concentration in μmol/1 which inhibits malondialdehyde formation by 50% (IC50). All the tested compounds have IC50's between 0.5 and 5 μM and are more active man Probucol, vitamin E and Vitamin C. Butyl hydroxytoluene (BHT) has an IC50 of 3.3 μM in this assay. Compound of formula (I) are thus useful for the treatment of disease states in which oxygen reactive species are involved. Table 2 Inhibition of rat liver homoeenates oxidation induced bv iron 2) Copper Oxidation of human low density lipoproteins CLOU " Plasma was obtained after low speed centrifugation of blood from donors. LDL (d= 1.006- 1.063 g/ml) were isolated by preparative ultracentrifugation in a salt 5 solution (NaBr, KBr). The isolated LDL fraction was dialysed against phosphate buffer. LDL oxidation was performed according to Esterbauer et al. (Continuous Monitoring of in Vitro Oxidation of Human Low Density Lipoprotein, Free Rad. 0 Res. Commun. £, 67-75, 1989). Briefly the LDL suspension (50-200μg protein/ml) was distributed in quartz cuvettes and kept at 37°C tiien a solution of G1CI2 was added at a final concentration of 5μM. The increase in optical density at 235 nm was recorded using a UV- visible spectrophotometer. The time course of oxidation was recorded over a period of 8 hours at 10 min intervals. Compounds to be tested 5 were dissolved in ethanol and added at die final concentration of 0.1 μM. Controls received ethanol only. The lag phase is prolonged by die presence of antioxidants. This method was validated widi Probucol and vitamin-E as reference antioxidants. The prolongation of the lag phase was used to quantify die antioxidant activity of 0 die compounds tested, tins prolongation was expressed in percent of the value measured in absence of exogen antioxidant (controls). The phosphonates of Formula (I) as noted in Table 3 prolong the lag phase compared to control. An inhibitory activity on LDL oxidation is tiius demonstrated 5 which is clearly superior to that of Probucol and vitamin E. Since these two antioxidants have been shown to be anti-atherosclerotic in animal models, die dierapeutic potential of phosphonates of Formula (I) is obvious. Table 3 Inhibition of LPL oxidation induced by copper Inhibition of Cholesterol and Cholesteryl Esters Synthesis The human intestinal cell line CaCo2 cells (ATCC HTB37) was used to study the effect of compounds of formula (I) on cholesterol synthesis. The cells were grown in 6 wells dishes (Falcon) in 2 ml of Dulbecco's modified Eagle culture medium (DMEM) supplemented widi 20% fetal calf serum (How). Cells were maintained at 37°C in a 5% CO2 atmosphere and the labelling experiment was done 8 days after cell plating. To die culture were added 10 μl of the etiianol solution of die compoimds to be tested. Control wells received lOμl of ethanol alone. One hour later 0.7 μCi of 14-C-acetate 53.4 mCi/mmol was added, labelling was continued for 4 hours and was stopped by washing the cell layer with chilled PBS. The cells were collected in 2ml of 0.01 N NaOH and 1 ml of PBS. Lipids were extracted by die Folch method and separated on silica gel TLC plates developed in petroleum ether: diediyl ether: acetic acid (70:30: 0.5). After exposition to iodine vapors, the bands corresponding to cholesterol and cholesteryl esters were scrapped off and radioactivity was measured in a liquid scintillator counter. The amount of radioactivity incorporated in cholesterol and cholesteryl esters in presence of compounds to be tested was compared to that of the control cells. HMGCoA reductase inhibitors such as simvastatin (lμM) served to validate die measurement of ^C-acetate incorporation in cholesterol and cholesteryl esters. All the compounds tested inhibited cholesterol and cholesteryl esters synthesis. Most of the compounds inhibited cholesteryl esters synthesis by more than 50% (Table 4). Phosphonates of formula (I) display an inhibitory activity on cholesterol and cholesteryl esters and can be considered as therapeutic agents in the treatment of hyperlipidemia and atiierosclerosis. Table 4 Inhibition of cholesterol and cholesteryl esters synthesis Calcium Entry Blocking activity of ketophosphonates Experiments were performed on aortic rings from male Sprague -Dawley rats (280-350g body weight) which were killed by stunning and exsanguination. Thoracic aortas were cleared of connective tissues and cut into rings of approximately 2mm in length. Each ring was mounted under a resting tension of 2g and was equilibrated for 1 hour at 37°C in a 10 ml organ bath containing a HEPES buffer Ringer solution (Buffer composition (mM): NaCl 139.0, KC15.0, MgCl23.7, D-Glucose 11.0, HEPES 5.0, pH 7.4) aerated with 95% O 2 :5% CO2. Maximal contractions were produced widiin 5-10 min exposure to lOμM Phenylephrine. The tissues were tiien washed widi a Ca +2 free HEPES buffer. After 30 min the tissue was depolarised widi KC1 (60mM).One hundred μl of the vehicle (10% DMSO) or compound solution (1 μM) were added 5 min later. The final concentration of DMSO was 1%. The tissues (n=2 per compound) were further equilibrated for 15 min in the presence of compounds prior to cumulative addition of Ca + 2 (0J-30 mM). The contractions to each concentration of calcium are calculated as a percentage of the second phenylephrine contraction and die EC30 (concentration of Ca 2+ producing a contraction 30% of the phenylephrine contraction) calculated. The potency index of each compound is expressed as die concentration ratio (calcium drug EC3ofrehicle EC30), where a potency index >1 indicates a compound effect The compounds of formula (I) are thus potentially useful in the treatment of cardiovascular diseases via tiieir calcium entry blocking activity. The primary indications of tiiese compounds would be the treatment of atherosclerosis, angina pectoris, congestive heart failure and hypertension. Table 5 Effect of compounds (I) on Ca + 2 induced contraction of K + depolarized rat aorta

Claims: CLAIMS 1. A compound of formula (I) where - X-, χ2 identical or different are straight or branched Cj to Cg alkyl groups, - Y is O or S, - Z-, 7?-, identical or different, are: - OR where R is H, a straight or branched Ci-Cβ alkyl group, - NR1R2 here R*, R 2 , identical or different are H or a straight or branched Ci-Cg alkyl group, - Z~, T-T- together may form a C2-Cg alkylidenedioxy group, - G is OH or a bioprecursor thereof; D is a saturated or unsaturated Cj-Ci \ alkylene chain in which one or more of the methylene groups can be replaced by a sulphur atom, an oxygen atom, a carbonyl group; optionally one or more methylene groups can be substituted by one or more halogen atoms (F, Cl or Br), Cj-g alkyl, phenyl, hydroxy or acyloxy groups, and salts, solvates and hydrates thereof. 2. A compound of formula (I) according to claim 1 where : D is A-C(O)-B, A-CH(OH)-B, A-CH 2 -B, (CH 2 )t-(CH=CH) n -(CH2)t or S- (CH 2 ) t , where - A is (CH 2 ) t , (CH=CH) n -CH=CX3, (CH 2 ) r CHX 3 , S-(CH 2 ) r (CH=CH) n , S-CX 4 X 5 , (CH=CH) n -CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX 3 , (CH 2 ) r C(O)-CHX 3 , S-CX 4 X 5 -C(O)-CHχ3, (CH=CH) n -CH=CH-CH(OH)-CHX3, (CH 2 )p-CH=CH-CH(OH)-CHχ3, (CH2) t -CH(OH)-CHχ3, S-(CH2) t -(CH=CH) n -CH(OH)-CHχ3, S-CX 4 X5-CH(0H)-CHX3 where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3, - X 3 is H, a straight or branched alkyl Cj-Cg group, a substituted or unsubstituted phenyl group, - X 4 , X-5 identical or different are H, a straight or branched C1-C4 alkyl group, - B is CH2, CH-X 6 , X 6 -C-X 7 , where X 6 and X 7 identical or different are halogen atoms (F,C1, Br), straight or branched Cj-Cg alkyl groups, a substituted or unsubstituted phenyl group; when A is (CH 2 ) t , (CH=CH) n -CH=CX 3 , (CH 2 ) t -CHχ3, S-(CH 2 ) t -(CH=CH) n , S-CX 4 X 5 , then B is also CH=CH-(CH 2 ) p , CH=CH-CHX<\ CH=CH-CX 6 X 7 , where p and X \ X 7 are defined as above. 3. A compound of formula (I) according to claim 1 in which D is A-C(O)-B in which A is (CH 2 ) t , (CH=CH) n -CH=CX3, (CH 2 ) r CHχ3, S-(CH 2 ) t -(CH=CH) n , S-CX 4 χ5, (CH=CH) n -CH=CH-C(O)-CHχ3, (CH2) p -CH-=CH-C(O)-CHχ3, (CH 2 )t-C(O)-CHχ3, S-CX 4 X 5 -C(O)-CHX , (CH=CH) n -CH=CH-CH(OH)-CHX3, (CH 2 ) p -CH=CH-CH(OH)-CHχ3, (CH 2 ) t -CH(OH)-CHχ3, S-(CH2)t-(CH=CH) n -CH(OH)-CHχ3, S-CX 4 X 5 -CH(OH)-CHX3, ^d where n is zero, 1 or 2, t is a number from 0 to 4, p is a number from 1 to 3, - χ3 is H, a straight or branched alkyl Cj-Cg group, a substituted or unsubstituted phenyl group, X 4 , X***- identical or different are H, a straight or branched C1-C4 alkyl group, and B is CH2, CH-X 6 , X 6 -C-X 7 , where X 6 and X 7 identical or different are halogen atoms (F,C1, Br), straight or branched C1-C6 alkyl groups, a substituted or unsubstituted phenyl group; when A is (CH 2 ) t , (CH=CH) n -CH=CX 3 , (CH 2 ) r CHχ3, S-(CH 2 ) r (CH=CH) n , S-CX 4 χ5, then B is also CH=CH-(CH 2 ) p , CH=CH-CHχ6, CH=CH-CX 6 X 7 , where p and X \ X 7 are as defined in claim 1. 4. A compound of formula (I) according to claim 1 in which D is -ACH(OH)-B- in which A and B are as described in claim 2. 5. A compound of formula (I) according to claim 1 in which D is A * -CH(O-CO-X 8 )-B' where A * is (CH 2 ) t , (CH=CH) n -CH=Cχ3, (CH 2 ) r CHχ3, S-(CH 2 )t-(CH=CH) n , S-CX 4 χ5, and B' is CH 2 , CH-χ6, χ6-C-X 7 , CH=CH-(CH 2 )p, CH=CH-CHX 6 , CH=CH-CX 6 X 7 where t, n, p, χ3, X 4 , χ5, χ6 ^d X 7 are as described in claim 2, and X 8 is a saturated or unsaturated Cj-Cgalkyl or alkenyl chain. 6. A compound of formula (I) according to claim 1 selected from the group comprising: dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1 -yl phosphonate, diediyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1-yl phosphonate, diisopropyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1 -yl phosphonate, dibutyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-l-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-lJ-dimethyl-2-oxo-3-buten-l-yl phosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-lJ-dimethyl-2-oxo-3-buten-l-yl phosphonate, diisopropyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)- 1 , 1 -dimethyl-2-oxo-3-buten- 1 -yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-l-methyl-2-oxo-3-buten-l-yl phosphonate, diediyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-l-methyl-2-oxo-3-buten-l-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-buten-l-yl phosphonate, diediyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-buten- 1 -yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(n-butyl)-2-oxo-3-buten- 1 -yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(n-pentyl)-2-oxo-3-buten-l-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten- 1 -yl phosphonate, diediyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-phenyl-3-buten- 1 -yl phosphonate, dimethyl 4- (3 ,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo- 1 -butyl phosphonate, diediyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-l-butyl phosphonate, dimethyl 4- (3 ,5-di-tert-butyl-4-hydroxyphenyl)- 1 , 1 -dimetiiy 1-2-oxo- 1 -butyl phosphonate, diediyl 4- (3,5-di-tert-butyl-4-hydroxypheny 1)- 1 , 1 -dimetiιyl-2-oxo- 1 -butyl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3,5-hexadien- 1 -yl phosphonate dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-lJ-dimethyl-2-oxo-3,5-hexadien-l- yl phosphonate diediyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)- 1 , 1 -dimetiιyl-2-oxo-3 ,5-hexadien- 1 -yl- phosphonate, dimediyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-l -ethyl phosphonate, N,N,N',N'-tetramethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1 -yl phosphonamide, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo- 1 -butyl phosphonate, dimethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen- 1 -yl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-5-hexen-l-yl phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-l-hexyl phosphonate, dimediyl 6-(3 ,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dioxo-hexyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) 3-ethyl-2-oxo-3-buten-l-yl phosphonate dimediyl 4-(3,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1 -yl phosphonate, diethyl 4-(3,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-buten-l-yl phosphonate, dimethyl 4-(3 ,5-di-tert-butyl-4-methoxyphenyl)-2-oxo-3-buten- 1 -yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten- 1-yl thionophosphonate, 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-l-yl](2-oxo-l,3,2- dioxaphosphorinan), dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-2-buten- 1-yl phosphonate, diediyl 4-(3 ,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-2-buten- 1-yl phosphonate, diediyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-l-edιyl phosphonate, diisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo- 1-edιyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl tiιio)-2-oxo-l-propyl phosphonate, diediyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-oxo-l-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo-l-propyl phosphonate diediyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-3,3-dimethyl-2-oxo- 1-propyl phosphonate dimethyl 5- (3 ,5-di-tert-butyl-4-hydrox yphenylthio)-2,4-dioxo- 1 -pentyl phosphonate, diediyl 5-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2,4-dioxo- 1-pentyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-3-buten- 1 -yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy- 1-butyl phosphonate, dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-hydroxy-l-ethyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-dihydroxy- 1 -butyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-hydroxy 1-propyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-l,3-butadien-l-yl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(acetyl oxy)-l -butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(hexanoyl oxy)-l -butyl phosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-pentenoyl oxy)-l-butyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-(acetyl oxy)-l-propyl phosphonate, dimethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl thio)-2-(hexanoyl oxy)-l-propyl phosphonate. A process for preparing compounds of formula (I) according to claim 3, where A is (CH 2 ) t , (CH=CH) n -CH=CX3, (CH 2 ) t -CHχ3, S-(CH 2 ) t -(CH=CH) n , S-CX 4 X*5 where n, t, χ , X 4 and X-*** are as described in claim 1 which consists in reacting the alkylphosphonates HI where B is CH2, CHX 6 , CX 6 X 7 and X 6 , X 7 , Y, Z 1 and Z 2 are as described in claim 1, with n-butyllithium or lithium diisopropylamide at a temperature between -78° and -40°, then reacting in situ the lithium anion of IE thus formed with die ester II II where X * **, X 2 , G are as described in claim 1 and A is (CH2) , (CH=CH) n -CH=CX3, (CΗ 2 ) t -CHχ3 ,S-(CH 2 ) r (CH=CH) n or S-CX 4 X 5 in tetrahydrofuran at a temperature between -78° C and 25°C. 8. A process for preparing compounds of formula (I) according to claim 3 where A is (CH=CH) n -CH=Cχ3 which consists in reacting an aldehyde of formula IV where G, X-, X 2 , n are as described in claim 1, with a ketophosphonate of formula V V where χ3, B, Y, Z-, Z 2 are as described in claim 1, in tetrahydrofuran in presence of titanium tetrachloride and N-methyl moφholine at a temperature between -20°C and 66°C. 9. A process for preparing compounds of formula (I) according to claim 3 in which A is (CH2)t-CHχ3, which consists in reacting the compound V V where χ3, B, Y, Z and Z 2 are as described in claim 1 first with sodium hydride and n-butyl lithium, men with the halide of formula VI where G, X-, X 2 , t are as described in claim 1, in tetrahydrofuran at a temperature between -30° and die boiling point of tetrahydrofuran (66°C). 10. A process for preparing compounds of formula (I) according to claim 3 where A is (CH=CH) n -CH=CH-C(O)-CHX3, (CH 2 ) p -CH=CH-C(O)-CHχ3, (CH 2 )t-C(O)-CHχ3, S-(CH 2 )t-(CH=CH) n -C(O)-CHX3 or S-CX 4 X 5 -C(O)-CHX3 where n, p, t, χ3, X 4 and X 5 are as described in claim 1 which consists in reacting compound V V where χ3, B, Y, Z-, Z 2 are as described in claim 1, first with sodium hydride then with n-butyl lithium or lithium diisopropylamide at a temperature between -78° and 0°, then widi ester VE where E is (CH=CH) n -CH=CH, (CH 2 ) p -CH=CH, (CH 2 ) t or S (CH2) r (CH=CH) n , S-CX 4 X 5 , n, p, t, X 4 , X 5 are as described in claim 1, in tetrahydrofuran at a temperature between -60° and 25°C°. 11. A process for preparing compounds of formula (I) according to claim 4 which consists in reducing die ketone functional group by a complex hydride, which is sodium borohydride or lithium borohydride in methanol, ethanol or isopropanol at a temperature between -20°C and die boiling point of the solvent. 12. A process for preparing compounds of formula (I) according to claim 5 which consists of esterification of the corresponding acyloxy-phosphonate compound, widi an appropriate acid anhydride (X^CO^O or acid chloride X^-CO'-Cl. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 in combination widi a pharmaceutically acceptable carrier. 14. A compound of formula (I) as claimed in claim 1 for use in therapy. 15. A compound of formula (I) as claimed in claim 1 for use in the treatment of atherosclerosis.

Inventors: AZOULAY RAYMOND, BENTZEN CRAIG L, DIEP VINH VAN, FLORET SIMON, GUYON-GELLIN YVES, MAECHLER PIERRE, NGUYEN LAN, NIESOR ERIC, PHAN HIEU, AZOULAY, RAYMOND, BENTZEN, CRAIG, L., DIEP, VINH, VAN, FLORET, SIMON, GUYON-GELLIN, YVES, MAECHLER, PIERRE, NGUYEN, LAN, NIESOR, ERIC, PHAN, HIEU
Applicants: AZOULAY RAYMOND, BENTZEN CRAIG L, DIEP VINH VAN, FLORET SIMON, GUYON GELLIN YVES, MAECHLER PIERRE, NGUYEN LAN, NIESOR ERIC, PHAN HIEU, SYMPHAR SA, AZOULAY, RAYMOND, BENTZEN, CRAIG, L., DIEP, VINH, VAN, FLORET, SIMON, GUYON-GELLIN, YVES, MAECHLER, PIERRE, NGUYEN, LAN, NIESOR, ERIC, PHAN, HIEU, SYMPHAR S.A.
Application year: 1994
Main classification: C07F9
IPC codes: A61K31, A61P9, C07F9